The present invention relates to novel phosphonic acid derivatives having endothelin-converting enzyme inhibiting activity, and is further directed to methods for producing the same and their use.
Endothelin is a vasoconstrictive peptide composed of 21 amino acid residues which was isolated from the culture supernatant of the endothelin cells of porcine aortas and whose structure was determined by Yanagisawa et al. [Yanagisawa et al., Nature, 332, 411-415 (1988)]. From the research on genes coding for endothelin, as the biosynthetic mechanism of endothelin, endothelin was deduced to be biosynthesized from an endothelin precursor through big endothelin (ibid.). The subsequent studies have revealed the presence of enzymes for converting big endothelin to endothelin (endothelin-converting enzymes) [Ikekawa et al., Biochem. Biophys. Res. Commu., 171, 669-675 (1990); and Okada et al., ibid., 171, 1192-1198 (1990)].
Endothelin has vasopressor activity, so that it is anticipated to be an intrinsic factor responsible for the control of circulatory systems and deduced to be related to hypertension, cardiac or cerebral circulatory diseases and renal diseases. Inhibitors for the endothelin-converting enzymes are potential therapeutic drugs for these diseases. At present, however, no endothelin-converting enzyme inhibiting substances other than phosphoramidon are reported.